Several publications and patent documents are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications and documents is incorporated by reference herein.
The human gut harbors an enormous number of bacteria, which have coevolved with the host and play important roles in the development of the immune system (1), resistance to intestinal infection (2), and nutrient metabolism and absorption (3). The coexistence of host and microbiota is due in large part to the equilibrium established between the host immune system and microbiota (4) through a variety of mechanisms (5). In the gastrointestinal tract, the large intestine harbors significantly more microbiota (1010-1012 bacteria per gram of feces) than the small intestine (105-107 bacteria per gram of feces) (6) and contains higher frequencies of FOXP3+ regulatory T cells (Treg), of which at least some have T cell antigen receptors (TCRs) specific for microbial antigens (7-9). Disruption of the equilibrium between the host immune system and microbiota can trigger inflammatory bowel disease in mouse models and, in humans, likely contributes to Crohn's disease and ulcerative colitis (10), in which the large intestine is the primary site of inflammation. While T cell responses have critical roles in inflammatory bowel diseases (10), it remains unclear how T cells migrate to the large intestine (11-13). Lymphocyte migration to the small intestine is dependent on retinoic acid-mediated induction of integrin α4β7 and CCR9 (14, 15). In addition, retinoic acid together with TGFβ induces the extrathymic differentiation of FOXP3+ Treg cells (16-19), which are essential for oral tolerance to food antigens (20). Retinoic acid is not, however, sufficient to induce T cell migration to the large intestine (11, 12), indicating that there is a separate mechanism for this process.